Psychostimulant drugs are addictive, and relapse to drug taking, even after prolonged periods of abstinence, is highly probable. The behavioral and neurochemical responses to psychostimulant drugs that change in concert with amount of drug exposure are thought to play an important role in addiction and relapse. A key hypothesis of Scientific Component 6 is that the seemingly diverse central nervous system alterations associated with addiction are coordinated in ways that are difficult to define by studying each in isolation. Two sets of selectively bred mice will be developed by the Animal Core Component 3 and used to help identify the genes and combinations of genes that influence methamphetamine (MA) self-administration and neuroadaptation. In Specific Aim 1, the genetic relationship between sensitization and self-administration will be examined in lines of mice bred for increased and reduced sensitivity to locomotor sensitization (a measure of neuroadaptation) produced by MA, and in separate lines bred for high and low oral MA self-administration; the operant intracranial MA self-administration model from Scientific Component 5 will be used to validate the oral self-administration model. In Specific Aim 2, full genome scans will be performed to identify genetic loci influencing each of the selected traits. In addition, data will be subjected to a search for epistatic (gene-gene) interactions to provide important insights into the genetic interplay that likely influences these complex traits. In Specific Aim 3, gene expression patterns will be examined in the brains of the selected lines using microarray methods on tissue from specific neuroanatomical locations to get a global picture of what gene expression differences may be associated with the differences in drug sensitivity. Neuroanatomic locations will be informed by Component 5 &pilot 8A. Finally, in Specific Aim 4, other traits that may be genetically correlated with the selection traits will be examined in the selected lines. For example, sensitivity to stress-induced reinstatement of MA-induced conditioned place preference will be examined;possible differences in impulsivity will be assessed using the Delay Discounting Procedure; neurochemical correlates will be examined in collaboration with Component 5. The preclinical genetic findings will be translated to our clinical investigators. Common implication of neuroanatomical pathways found across the Scientific Components could lead to the identification of coordinated pathways that influence addiction.